Learning of the same task subserved by substantially different mechanisms between patients with body dysmorphic disorder and healthy individuals.

It has remained unclear whether individuals with psychiatric disorders involving altered visual processing employ similar neuronal mechanisms during perceptual learning of a visual task. We investigated this question by training patients with body dysmorphic disorder, a psychiatric disorder characterized by distressing or impairing preoccupation with nonexistent or slight defects in one's physical appearance, and healthy controls on a visual detection task for human faces with low spatial frequency components. Brain activation during task performance was measured with functional magnetic resonance imaging before the beginning and after the end of behavioral training. Both groups of participants improved performance on the trained task to a similar extent. However, neuronal changes in the fusiform face area were substantially different between groups such that activation for low spatial frequency faces in the right fusiform face area increased after training in body dysmorphic disorder patients but decreased in controls. Moreover, functional connectivity between left and right fusiform face area decreased after training in patients but increased in controls. Our results indicate that neuronal mechanisms involved in perceptual learning of a face detection task differ fundamentally between body dysmorphic disorder patients and controls. Such different neuronal mechanisms in body dysmorphic disorder patients might reflect the brain's adaptations to altered functions imposed by the psychiatric disorder.

Transfer of Tactile Learning from Trained to Untrained Body Parts Supported by Cortical Coactivation in Primary Somatosensory Cortex.

A pioneering study by Volkmann (1858) revealed that training on a tactile discrimination task improved task performance, indicative of tactile learning, and that such tactile learning transferred from trained to untrained body parts. However, the neural mechanisms underlying tactile learning and transfer of tactile learning have remained unclear. We trained groups of human subjects (female and male) in daily sessions on a tactile discrimination task either by stimulating the palm of the right hand or the sole of the right foot. Task performance before training was similar between the palm and sole. Posttraining transfer of tactile learning was greater from the trained right sole to the untrained right palm than from the trained right palm to the untrained right sole. Functional magnetic resonance imaging (fMRI) and multivariate pattern classification analysis revealed that the somatotopic representation of the right palm in contralateral primary somatosensory cortex (SI) was coactivated during tactile stimulation of the right sole. More pronounced coactivation in the cortical representation of the right palm was associated with lower tactile performance for tactile stimulation of the right sole and more pronounced subsequent transfer of tactile learning from the trained right sole to the untrained right palm. In contrast, coactivation of the cortical sole representation during tactile stimulation of the palm was less pronounced and no association with tactile performance and subsequent transfer of tactile learning was found. These results indicate that tactile learning may transfer to untrained body parts that are coactivated to support tactile learning with the trained body part.SIGNIFICANCE STATEMENT Perceptual skills such as the discrimination of tactile cues can improve by means of training, indicative of perceptual learning and sensory plasticity. However, it has remained unclear whether and if so, how such perceptual learning can occur if the training task is very difficult. Here, we show for tactile perceptual learning that the representation of the palm of the hand in primary somatosensory cortex (SI) is coactivated to support learning of a difficult tactile discrimination task with tactile stimulation of the sole of the foot. Such cortical coactivation of an untrained body part to support tactile learning with a trained body part might be critically involved in the subsequent transfer of tactile learning between the trained and untrained body parts.

Reward does not facilitate visual perceptual learning until sleep occurs.

A growing body of evidence indicates that visual perceptual learning (VPL) is enhanced by reward provided during training. Another line of studies has shown that sleep following training also plays a role in facilitating VPL, an effect known as the offline performance gain of VPL. However, whether the effects of reward and sleep interact on VPL remains unclear. Here, we show that reward interacts with sleep to facilitate offline performance gains of VPL. First, we demonstrated a significantly larger offline performance gain over a 12-h interval including sleep in a reward group than that in a no-reward group. However, the offline performance gains over the 12-h interval without sleep were not significantly different with or without reward during training, indicating a crucial interaction between reward and sleep in VPL. Next, we tested whether neural activations during posttraining sleep were modulated after reward was provided during training. Reward provided during training enhanced rapid eye movement (REM) sleep time, increased oscillatory activities for reward processing in the prefrontal region during REM sleep, and inhibited neural activation in the untrained region in early visual areas in non-rapid eye movement (NREM) and REM sleep. The offline performance gains were significantly correlated with oscillatory activities of visual processing during NREM sleep and reward processing during REM sleep in the reward group but not in the no-reward group. These results suggest that reward provided during training becomes effective during sleep, with excited reward processing sending inhibitory signals to suppress noise in visual processing, resulting in larger offline performance gains over sleep.

Are sleep disturbances a cause or consequence of autism spectrum disorder?

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms such as atypical social communication, stereotyped behaviors, and restricted interests. One of the comorbid symptoms of individuals with ASD is sleep disturbance. There are two major hypotheses regarding the neural mechanism underlying ASD, i.e., the excitation/inhibition (E/I) imbalance and the altered neuroplasticity hypotheses. However, the pathology of ASD remains unclear due to inconsistent research results. This paper argues that sleep is a confounding factor, thus, must be considered when examining the pathology of ASD because sleep plays an important role in modulating the E/I balance and neuroplasticity in the human brain. Investigation of the E/I balance and neuroplasticity during sleep might enhance our understanding of the neural mechanisms of ASD. It may also lead to the development of neurobiologically informed interventions to supplement existing psychosocial therapies.

Early Visual Cortex Stimulation Modifies Well-Consolidated Perceptual Gains.

Perception thresholds can improve through repeated practice with visual tasks. Can an already acquired and well-consolidated perceptual skill be noninvasively neuromodulated, unfolding the neural mechanisms involved? Here, leveraging the susceptibility of reactivated memories ranging from synaptic to systems levels across learning and memory domains and animal models, we used noninvasive brain stimulation to neuromodulate well-consolidated reactivated visual perceptual learning and reveal the underlying neural mechanisms. Subjects first encoded and consolidated the visual skill memory by performing daily practice sessions with the task. On a separate day, the consolidated visual memory was briefly reactivated, followed by low-frequency, inhibitory 1 Hz repetitive transcranial magnetic stimulation over early visual cortex, which was individually localized using functional magnetic resonance imaging. Poststimulation perceptual thresholds were measured on the final session. The results show modulation of perceptual thresholds following early visual cortex stimulation, relative to control stimulation. Consistently, resting state functional connectivity between trained and untrained parts of early visual cortex prior to training predicted the magnitude of perceptual threshold modulation. Together, these results indicate that even previously consolidated human perceptual memories are susceptible to neuromodulation, involving early visual cortical processing. Moreover, the opportunity to noninvasively neuromodulate reactivated perceptual learning may have important clinical implications.

Gray Matter Volume in Different Cortical Structures Dissociably Relates to Individual Differences in Capacity and Precision of Visual Working Memory.

Visual working memory (VWM) refers to our ability to selectively maintain visual information in a mental representation. While cognitive limits of VWM greatly influence a variety of mental operations, it remains controversial whether the quantity or quality of representations in mind constrains VWM. Here, we examined behavior-to-brain anatomical relations as well as brain activity to brain anatomy associations with a "neural" marker specific to the retention interval of VWM. Our results consistently indicated that individuals who maintained a larger number of items in VWM tended to have a larger gray matter (GM) volume in their left lateral occipital region. In contrast, individuals with a superior ability to retain with high precision tended to have a larger GM volume in their right parietal lobe. These results indicate that individual differences in quantity and quality of VWM may be associated with regional GM volumes in a dissociable manner, indicating willful integration of information in VWM may recruit separable cortical subsystems.

Visual perceptual learning of a primitive feature in human V1/V2 as a result of unconscious processing, revealed by decoded functional MRI neurofeedback (DecNef).

Although numerous studies have shown that visual perceptual learning (VPL) occurs as a result of exposure to a visual feature in a task-irrelevant manner, the underlying neural mechanism is poorly understood. In a previous psychophysical study (Watanabe et al., 2002), subjects were repeatedly exposed to a task-irrelevant Sekuler motion display that induced the perception of not only the local motions, but also a global motionmoving in the direction of the spatiotemporal average of the local motion vectors. As a result of this exposure, subjects enhanced their sensitivity only to the local moving directions, suggesting that early visual areas (V1/V2) that process local motions are involved in task-irrelevant VPL. However, this hypothesis has never been tested directly using neuronal recordings. Here, we employed a decoded neurofeedback technique (DecNef) using functional magnetic resonance imaging in human subjects to examine the involvement of early visual areas (V1/V2) in task-irrelevant VPL of local motion within a Sekuler motion display. During the DecNef training, subjects were trained to induce the activity patterns in V1/V2 that were similar to those evoked by the actual presentation of the Sekuler motion display. The DecNef training was conducted with neither the actual presentation of the display nor the subjects' awareness of the purpose of the experiment. After the experiment, subjects reported that they neither perceived nor imagined the trained motion during the DecNef training. As a result of DecNef training, subjects increased their sensitivity to the local motion directions, but not specifically to the global motion direction. Neuronal changes related to DecNef training were confined to V1/V2. These results suggest that V1/V2 are involved in exposure-based task-irrelevant VPL of local motion.

Feature-Specific Awake Reactivation in Human V1 after Visual Training.

Brain activity patterns exhibited during task performance have been shown to spontaneously reemerge in the following restful awake state. Such "awake reactivation" has been observed across higher-order cortex for complex images or associations. However, it is still unclear whether the reactivation extends to primary sensory areas that encode simple stimulus features. To address this question, we trained human subjects from both sexes on a particular visual feature (Gabor orientation) and tested whether this feature will be reactivated immediately after training. We found robust reactivation in human V1 that lasted for at least 8 min after training offset. This effect was not present in higher retinotopic areas, such as V2, V3, V3A, or V4v. Further analyses suggested that the amount of awake reactivation was related to the amount of performance improvement on the visual task. These results demonstrate that awake reactivation extends beyond higher-order areas and also occurs in early sensory cortex.SIGNIFICANCE STATEMENT How do we acquire new memories and skills? New information is known to be consolidated during offline periods of rest. Recent studies suggest that a critical process during this period of consolidation is the spontaneous reactivation of previously experienced patterns of neural activity. However, research in humans has mostly examined such reactivation processes in higher-order cortex. Here we show that awake reactivation occurs even in the primary visual cortex V1 and that this reactivation is related to the amount of behavioral learning. These results pinpoint awake reactivation as a process that likely occurs across the entire human brain and could play an integral role in memory consolidation.

Toward a comprehensive understanding of the neural mechanisms of decoded neurofeedback.

Real-time functional magnetic resonance imaging (fMRI) neurofeedback is an experimental framework in which fMRI signals are presented to participants in a real-time manner to change their behaviors. Changes in behaviors after real-time fMRI neurofeedback are postulated to be caused by neural plasticity driven by the induction of specific targeted activities at the neuronal level (targeted neural plasticity model). However, some research groups argued that behavioral changes in conventional real-time fMRI neurofeedback studies are explained by alternative accounts, including the placebo effect and physiological artifacts. Recently, decoded neurofeedback (DecNef) has been developed as a result of adapting new technological advancements, including implicit neurofeedback and fMRI multivariate analyses. DecNef provides strong evidence for the targeted neural plasticity model while refuting the abovementioned alternative accounts. In this review, we first discuss how DecNef refutes the alternative accounts. Second, we propose a model that shows how targeted neural plasticity occurs at the neuronal level during DecNef training. Finally, we discuss computational and empirical evidence that supports the model. Clarification of the neural mechanisms of DecNef would lead to the development of more advanced fMRI neurofeedback methods that may serve as powerful tools for both basic and clinical research.

Differential Activation Patterns in the Same Brain Region Led to Opposite Emotional States.

In human studies, how averaged activation in a brain region relates to human behavior has been extensively investigated. This approach has led to the finding that positive and negative facial preferences are represented by different brain regions. However, using a functional magnetic resonance imaging (fMRI) decoded neurofeedback (DecNef) method, we found that different patterns of neural activations within the cingulate cortex (CC) play roles in representing opposite directions of facial preference. In the present study, while neutrally preferred faces were presented, multi-voxel activation patterns in the CC that corresponded to higher (or lower) preference were repeatedly induced by fMRI DecNef. As a result, previously neutrally preferred faces became more (or less) preferred. We conclude that a different activation pattern in the CC, rather than averaged activation in a different area, represents and suffices to determine positive or negative facial preference. This new approach may reveal the importance of an activation pattern within a brain region in many cognitive functions.

Trained-feature-specific offline learning by sleep in an orientation detection task.

Training-induced performance gains in a visual perceptual learning (VPL) task that take place during sleep are termed "offline performance gains." Offline performance gains of VPL so far have been reported in the texture discrimination task and other discrimination tasks. This raises the question as to whether offline performance gains on VPL occur exclusively in discrimination tasks. The present study examined whether offline performance gains occur in detection tasks. In Experiment 1, subjects were trained on a Gabor orientation detection task. They were retested after a 12-hr interval, which included either nightly sleep or only wakefulness. Offline performance gains occurred only after sleep on the trained orientation, not on an untrained orientation. In Experiment 2, we tested whether offline performance gains in the detection task occur over a nap using polysomnography. Moreover, we tested whether sigma activity during non-rapid eye movement (NREM) sleep recorded from occipital electrodes, previously implicated in offline performance gains of the texture discrimination task, was associated with the degree of offline performance gains of the Gabor orientation detection task. We replicated offline performance gains on the trained orientation in the detection task over the nap. Sigma activity during NREM sleep was significantly larger in the occipital electrodes relative to control electrodes in correlation with offline performance gains. The results suggest that offline performance gains occur over the sleep period generally in VPL. Moreover, sigma activity in the occipital region during NREM sleep may play an important role in offline performance gains of VPL.

Factors predictive of the efficacy of bezafibrate therapy in patients with primary sclerosing cholangitis.

AIM: Primary sclerosing cholangitis (PSC) is a rare cholestatic disease. We previously reported the effects of bezafibrate on elevated hepatobiliary enzyme levels in patients with this disease both retrospectively and prospectively. In this study, we assessed factors predictive of bezafibrate efficacy. METHODS: Twenty-five patients with PSC, who underwent bezafibrate therapy (400 mg per day) from November 2006 to June 2015, were evaluated. Treatment was judged as being effective if the levels of all of the hepatobiliary enzymes decreased after 12 weeks. We investigated the patients' characteristics, disease history, concomitant medications, liver function, and liver stiffness. RESULTS: The efficacy rate of bezafibrate was 60% (15/25 patients). The efficacy rate in patients graded as Child-Pugh class A was significantly higher (75% [15/20]) than that in patients graded as class B (0% [0/5], P < 0.01). Non-responders had higher liver stiffness values (18.0 vs. 8.8 kPa, P = 0.19), and concomitantly used ursodeoxycholic acid more frequently (100% vs. 73%, P = 0.12) than responders. CONCLUSIONS: We could not elucidate the factors predictive for bezafibrate efficacy for the treatment of PSC. However, bezafibrate was more effective for patients with preserved liver function (Child-Pugh class A) when it was prescribed before progression of liver fibrosis and failure of ursodeoxycholic acid therapy.

Neuroimaging Evidence for 2 Types of Plasticity in Association with Visual Perceptual Learning.

Visual perceptual learning (VPL) is long-term performance improvement as a result of perceptual experience. It is unclear whether VPL is associated with refinement in representations of the trained feature (feature-based plasticity), improvement in processing of the trained task (task-based plasticity), or both. Here, we provide empirical evidence that VPL of motion detection is associated with both types of plasticity which occur predominantly in different brain areas. Before and after training on a motion detection task, subjects' neural responses to the trained motion stimuli were measured using functional magnetic resonance imaging. In V3A, significant response changes after training were observed specifically to the trained motion stimulus but independently of whether subjects performed the trained task. This suggests that the response changes in V3A represent feature-based plasticity in VPL of motion detection. In V1 and the intraparietal sulcus, significant response changes were found only when subjects performed the trained task on the trained motion stimulus. This suggests that the response changes in these areas reflect task-based plasticity. These results collectively suggest that VPL of motion detection is associated with the 2 types of plasticity, which occur in different areas and therefore have separate mechanisms at least to some degree.

Reward eliminates retrieval-induced forgetting.

Although it is well known that reward enhances learning and memory, how extensively such enhancement occurs remains unclear. To address this question, we examined how reward influences retrieval-induced forgetting (RIF) in which the retrieval of a nonpracticed item under the same category as a practiced item is worse than the retrieval of a nonpracticed item outside the category. Subjects were asked to try to encode category-exemplar pairs (e.g., FISH-salmon). Then, they were presented with a category name and a two-letter word stem (e.g., FISH-sa) and were asked to complete an encoded word (retrieval practice). For a correct response, apple juice was given as a reward in the reward condition and a beeping sound was presented in the no-reward condition. Finally, subjects were asked to report whether each exemplar had been presented in the first phase. RIF was replicated in the no-reward condition. However, in the reward condition, RIF was eliminated. These results suggest that reward enhances processing of retrieval of unpracticed members by mechanisms such as spreading activation within the same category, irrespective of whether items were practiced or not.

Indications for endoscopic ultrasonography (EUS)-guided biliary intervention: Does EUS always come after failed endoscopic retrograde cholangiopancreatography?

BACKGROUND AND AIM: Endoscopic ultrasonography-guided biliary drainage (EUS-BD), first reported as an alternative to percutaneous transhepatic biliary drainage (PTBD) after failed endoscopic retrograde cholangiopancreatography (ERCP), is increasingly reported as a primary procedure without failed ERCP. The present study aims to evaluate the outcomes of therapeutic biliary ERCP and to compare the safety and effectiveness of primary EUS-BD with those of ERCP, rescue EUS-BD and PTBD. METHODS: We retrospectively studied therapeutic biliary ERCP as well as subsequent rescue PTBD and EUS-BD. Additionally, indications, safety and technical success of primary EUS-BD were evaluated. RESULTS: Between August 2013 and September 2015, a total of 520 therapeutic biliary ERCP with a native papilla were analyzed. We encountered 23 cases with inaccessible papilla and 22 cases with failed cannulation, which were rescued by 21 PTBD, 16 EUS-BD and two repeat ERCP. Additionally, 40 primary EUS-BD were carried out during the same period as a result of 10 recurrent cholangitis cases after transpapillary drainage, five outside failed cannulation, four altered anatomy, two history of ERCP-related adverse events (AE), two technical difficulties in stenting under enteroscopy-assisted ERCP and 17 on study protocol. Technical success and AE rates were 95.6% and 14.5% in ERCP, 90.5% and 33.3% in rescue PTBD, 93.8% and 18.8% in rescue EUS-BD, and 95.0% and 22.5% in primary EUS-BD, respectively. CONCLUSIONS: Rescue EUS-BD was used in 3.1% among all ERCP. Given the comparable technical success and AE rates of both primary and rescue EUS-BD, primary EUS-BD without failed ERCP can be a treatment option if it provides advantages over ERCP.

Real-Time Strategy Video Game Experience and Visual Perceptual Learning.

Visual perceptual learning (VPL) is defined as long-term improvement in performance on a visual-perception task after visual experiences or training. Early studies have found that VPL is highly specific for the trained feature and location, suggesting that VPL is associated with changes in the early visual cortex. However, the generality of visual skills enhancement attributable to action video-game experience suggests that VPL can result from improvement in higher cognitive skills. If so, experience in real-time strategy (RTS) video-game play, which may heavily involve cognitive skills, may also facilitate VPL. To test this hypothesis, we compared VPL between RTS video-game players (VGPs) and non-VGPs (NVGPs) and elucidated underlying structural and functional neural mechanisms. Healthy young human subjects underwent six training sessions on a texture discrimination task. Diffusion-tensor and functional magnetic resonance imaging were performed before and after training. VGPs performed better than NVGPs in the early phase of training. White-matter connectivity between the right external capsule and visual cortex and neuronal activity in the right inferior frontal gyrus (IFG) and anterior cingulate cortex (ACC) were greater in VGPs than NVGPs and were significantly correlated with RTS video-game experience. In both VGPs and NVGPs, there was task-related neuronal activity in the right IFG, ACC, and striatum, which was strengthened after training. These results indicate that RTS video-game experience, associated with changes in higher-order cognitive functions and connectivity between visual and cognitive areas, facilitates VPL in early phases of training. The results support the hypothesis that VPL can occur without involvement of only visual areas. Significance statement: Although early studies found that visual perceptual learning (VPL) is associated with involvement of the visual cortex, generality of visual skills enhancement by action video-game experience suggests that higher-order cognition may be involved in VPL. If so, real-time strategy (RTS) video-game experience may facilitate VPL as a result of heavy involvement of cognitive skills. Here, we compared VPL between RTS video-game players (VGPs) and non-VGPs (NVGPs) and investigated the underlying neural mechanisms. VGPs showed better performance in the early phase of training on the texture discrimination task and greater level of neuronal activity in cognitive areas and structural connectivity between visual and cognitive areas than NVGPs. These results support the hypothesis that VPL can occur beyond the visual cortex.

Outcome of Long-term Maintenance Steroid Therapy Cessation in Patients With Autoimmune Pancreatitis: A Prospective Study.

OBJECTIVE: To predict the duration of steroid maintenance therapy required to achieve good prognosis in patients with autoimmune pancreatitis. PATIENTS AND METHODS: The study sample comprised 21 patients with autoimmune pancreatitis who met the following criteria: (1) they received steroid therapy (ST) for at least 3 years without clinical relapse; and (2) immunoglobulin (Ig) G<1600 mg/dL was observed in the past year with a prednisolone maintenance dose ≤5 mg. All patients could be diagnosed with international consensus diagnostic criteria. Patients were prospectively followed up after tapering and cessation of steroids. Clinical relapse was defined as the need to resume ST. Serological relapse was defined as having an IgG level of >1600 mg/dL. RESULTS: During the 43-month (range, 19 to 48 mo) follow-up period, clinical relapse occurred in 10 patients: pancreatic lesion in 4; coronary lesion in 2; submandibular lesion in 1; both pulmonary and renal lesions in 1; pulmonary, retroperitoneal, and submandibular lesions in 1; and bronchial asthma in 1. Serological relapse was observed in 12 patients. Although clinical and serological relapse occurred concomitantly in 3 patients, serological relapse preceded clinical relapse in 4 patients. Five patients experienced serological relapse alone, and no clinical or serological relapse occurred in 6 patients. According to Cox proportional hazard analysis, the duration of ST before tapering was a significant predictive parameter (hazard ratio, 0.969/month; 95% confidence interval, 0.940-0.998; P=0.038). CONCLUSIONS: ST cessation resulted in a high rate of clinical relapses, even in patients with long-term maintenance therapy. Therefore, it appears desirable to continue steroid maintenance therapy for a period >3 years to prevent relapse.

Perceptual learning: toward a comprehensive theory.

Visual perceptual learning (VPL) is long-term performance increase resulting from visual perceptual experience. Task-relevant VPL of a feature results from training of a task on the feature relevant to the task. Task-irrelevant VPL arises as a result of exposure to the feature irrelevant to the trained task. At least two serious problems exist. First, there is the controversy over which stage of information processing is changed in association with task-relevant VPL. Second, no model has ever explained both task-relevant and task-irrelevant VPL. Here we propose a dual plasticity model in which feature-based plasticity is a change in a representation of the learned feature, and task-based plasticity is a change in processing of the trained task. Although the two types of plasticity underlie task-relevant VPL, only feature-based plasticity underlies task-irrelevant VPL. This model provides a new comprehensive framework in which apparently contradictory results could be explained.

Advances in visual perceptual learning and plasticity.

Visual perceptual learning (VPL) is defined as a long-term improvement in performance on a visual task. In recent years, the idea that conscious effort is necessary for VPL to occur has been challenged by research suggesting the involvement of more implicit processing mechanisms, such as reinforcement-driven processing and consolidation. In addition, we have learnt much about the neural substrates of VPL and it has become evident that changes in visual areas and regions beyond the visual cortex can take place during VPL.

Improving vision among older adults: behavioral training to improve sight.

A major problem for the rapidly growing population of older adults (age 65 and over) is age-related declines in vision, which have been associated with increased risk of falls and vehicle crashes. Research suggests that this increased risk is associated with declines in contrast sensitivity and visual acuity. We examined whether a perceptual-learning task could be used to improve age-related declines in contrast sensitivity. Older and younger adults were trained over 7 days using a forced-choice orientation-discrimination task with stimuli that varied in contrast with multiple levels of additive noise. Older adults performed as well after training as did college-age younger adults prior to training. Improvements transferred to performance for an untrained stimulus orientation and were not associated with changes in retinal illuminance. Improvements in far acuity in younger adults and in near acuity in older adults were also found. These findings indicate that behavioral interventions can greatly improve visual performance for older adults.